Radionuclide imaging of myocardial perfusion, function, and viability has been established for decades and remains a robust, evidence-based and broadly available means for clinical workup and therapeutic guidance in ischemic heart disease. Yet, powerful alternative modalities have emerged for this purpose, and their growth has resulted in increasing competition. But the potential of the tracer principle goes beyond the assessment of physiology and function, towards the interrogation of biology and molecular pathways. This is a unique selling point of radionuclide imaging, which has been under-recognized in cardiovascular medicine until recently. Now, molecular imaging methods for the detection of myocardial infiltration, device infection and cardiovascular inflammation are successfully gaining clinical acceptance. This is further strengthened by the symbiotic quest of cardiac imaging and therapy for an increasing implementation of molecular-targeted procedures, where specific therapeutic interventions require specific diagnostic guidance towards the most suitable candidates. This review will summarize the current advent of clinical cardiovascular molecular imaging and highlight its transformative contribution to the evolution of cardiovascular therapy beyond mechanical interventions and broad "blockbuster" medication, towards a future of novel, individualized molecular targeted and molecular imaging-guided therapies.

In randomized clinical trials (RCTs), no survival benefit has been observed for selective internal radiotherapy (SIRT) over sorafenib in patients with advanced hepatocellular carcinoma (aHCC). This study aimed to assess by means of a meta-analysis whether overall survival (OS) with SIRT, as monotherapy or followed by sorafenib, is non-inferior to sorafenib, and compare safety profiles for patients with aHCC. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library up to February 2019 to identify RCTs comparing SIRT as monotherapy, or followed by sorafenib, to sorafenib monotherapy among patients with aHCC. The main outcomes were OS and frequency of treatment-related severe adverse events (AEs grade ≥3). The per-protocol population was the primary analysis population. A non-inferiority margin of 1.08 in terms of hazard ratio (HR) was pre-specified for the upper boundary of 95% confidence interval (CI) for OS. Pre-specified subgroup analyses were performed. Results: Three RCTs, involving 1,243 patients, comparing sorafenib with SIRT (SIRveNIB and SARAH) or SIRT followed by sorafenib (SORAMIC), were included. After randomization, 411/635 (64.7%) patients allocated to SIRT and 522/608 (85.8%) allocated to sorafenib completed the studies without major protocol deviations. Median OS with SIRT, whether or not followed by sorafenib, was non-inferior to sorafenib (10.2 and 9.2 months, [HR 0.91, 95% CI 0.78–1.05]). Treatment-related severe adverse events were reported in 149/515 patients (28.9%) who received SIRT and 249/575 (43.3%) who received sorafenib only (p<0.01). Conclusion: SIRT as initial therapy for aHCC is non-inferior to sorafenib in terms of OS, and offers a better safety profile.

Anal squamous cell carcinoma is a rare tumor. Chemo-radiotherapy yields a 50% 3-year relapse-free survival rate in advanced anal cancer, so improved predictive markers and therapeutic options are needed. High-throughput proteomics and whole-exome sequencing were performed in 46 paraffin samples from anal squamous cell carcinoma patients. Hierarchical clustering was used to establish groups de novo. Then, probabilistic graphical models were used to study the differences between groups of patients at the biological process level. A molecular classification into two groups of patients was established, one group with increased expression of proteins related to adhesion, T lymphocytes and glycolysis; and the other group with increased expression of proteins related to translation and ribosomes. The functional analysis by the probabilistic graphical model showed that these two groups presented differences in metabolism, mitochondria, translation, splicing and adhesion processes. Additionally, these groups showed different frequencies of genetic variants in some genes, such as ATM, SLFN11 and DST. Finally, genetic and proteomic characteristics of these groups suggested the use of some possible targeted therapies, such as PARP inhibitors or immunotherapy.

Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was because of a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well as DFMO-induced preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.

Apple is in the middle of a legal fight with the FBI over creating a 'back door' to unlock a terrorist's iPhone.

Keisuke Mori
Apr 29, 2020; 0:jlr.RA120000803v1-jlr.RA120000803
Research Articles

Gemma Cadby
Apr 1, 2020; 61:537-545
Patient-Oriented and Epidemiological Research

Naoko Sawada
Apr 14, 2020; 0:jlr.RA119000312v1-jlr.RA119000312
Research Articles

Haibo Jiang
Apr 2, 2020; 0:jlr.ILR120000783v1-jlr.ILR120000783
Images in Lipid Research

Macworld UK’s Acting Editor David Price takes the reins for this edition, and is joined by Online Editor of Computerworld UK Scott Carey to chat about billions and billions of pounds and the acquisition of ARM by SoftBank. Second up, Staff Writer at PC Advisor and Macworld UK Christopher Minasians plugs in to the haunting world of graphics cards and makes sense of it all for the rest of us. Digital Arts Staff Writer Mimi Launder then explains why Twitter has slapped a troll right in the face in order to stand up to Internet bullying.  

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After a lengthy hiatus we are back to FINALLY talk about the iPhone X. Computerworld UK editor Scott Carey is in the hosting chair to chat with Chris Martin, reviews editor at Tech Advisor and Macworld UK, now that we have got our hands on one. Chris talks us through what he likes and dislikes so far about the pricey smartphone.

Then Miriam Harris, staff writer at Digital Arts jumps in to discuss the design principles behind driverless cars and what we can expect in the future (17:00).

Finally, pod debutante Caroline Vanier, senior staff writer at Tech Advisor France talks about the FairPhone and if it is a new model for the smart phone industry (28:00).

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Back with a bang as Computerworld editor Scott Carey leads the squad into the cauldron of convo. Christina Mercer explains why her beau Elon Musk took a car into space, Sean Bradley on that bursting Bitcoin bubble, and David Price to tell us all how Apple can charge even more for its stuff and keep on making record profit.

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Oxidized low-density lipoprotein (oxLDL) is a known risk factor for atherogenesis. This study aimed to reveal structural features of oxLDL present in human circulation related to atherosclerosis. When LDL was fractionated on an anion-exchange column, in vivo-oxLDL, detected by the anti-oxidized phosphatidylcholine (oxPC) monoclonal antibody, was recovered in flow-through and electronegative LDL (LDL(-)) fractions. The amount of the electronegative in vivo-oxLDL, namely oxLDL in LDL(-) fraction, present in patients with acute myocardial infarction (AMI) was three-fold higher than that observed in healthy subjects. Surprisingly, LDL(-) fraction contained apoA1 in addition to apoB, and HDL-sized particles were observed with transmission electron microscopy. In LDL(-) fractions, acrolein adducts were identified at all lysine residues in apoA1, with only a small number of acrolein-modified residues were identified in apoB. The amount of oxPC adducts of apoB was higher in LDL(-) than in L1 fraction as determined using western blotting. The electronegative in vivo-oxLDL was immunologically purified from the LDL(-) fraction with an anti-oxPC monoclonal antibody. Majority of PC species was not oxidized, whereas oxPC and lysoPC did not accumulate. Here, we propose that there are two types of in vivo-oxLDL in human circulating plasma and the electronegative in vivo-oxLDL accompanies oxidized HDL.

The yeast protein Mpo1 belongs to a protein family that is widely conserved in bacteria, fungi, protozoa, and plants, and is the only protein of this family whose function has so far been elucidated. Mpo1 is an Fe²⁺-dependent dioxygenase that catalyzes the α-oxidation reaction of 2-hydroxy (2-OH) long-chain FAs produced in the degradation pathway of the long-chain base phytosphingosine. However, several biochemical characteristics of Mpo1, such as its catalytic residues, membrane topology, and substrate specificity, remain unclear. Here, we report that yeast Mpo1 contains two transmembrane domains and that both its N- and C-terminal regions are exposed to the cytosol. Mutational analyses revealed that three histidine residues conserved in the Mpo1 family are especially important for Mpo1 activity, suggesting that they may be responsible for the formation of coordinate bonds with Fe²⁺. We found that, in addition to activity toward 2-OH long-chain FAs, Mpo1 also exhibits activity toward 2-OH very-long-chain FAs derived from the FA moiety of sphingolipids. These results indicate that Mpo1 is involved in the metabolism of long-chain to very-long-chain 2-OH FAs produced in different pathways. We noted that the growth of mpo1 cells is delayed upon carbon deprivation, suggesting that the Mpo1-mediated conversion of 2-OH FAs to non-hydroxy FAs is important for utilizing 2-OH FAs as a carbon source under carbon starvation. Our findings help to elucidate the as-yet-unknown functions and activities of other Mpo1 family members.

Accumulation and propagation of hyperphosphorylated tau (p-tau) is a common neuropathological hallmark associated with neurodegeneration of Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and related tauopathies. Extracellular vesicles, specifically exosomes, have recently been demonstrated to participate in mediating tau propagation in brain. Exosomes produced by human induced pluripotent stem cell (iPSC)-derived neurons expressing mutant Tau (mTau), containing the P301L and V337M Tau mutations of FTDP-17, possess the ability to propagate p-tau pathology after injection into mouse brain.  To gain an understanding of the mTau exosome cargo involved in tau pathogenesis, these pathogenic exosomes were analyzed by proteomics and bioinformatics. The data showed that mTau expression dysregulates the exosome proteome to result in (1) proteins uniquely present only in mTau, and not control exosomes, (2) the absence of proteins in mTau exosomes, uniquely present in control exosomes, and (3) shared proteins which were significantly up-regulated or down-regulated in mTau compared to control exosomes. Notably, mTau exosomes (not control exosomes) contain ANP32A (also known as I1PP2A), an endogenous inhibitor of the PP2A phosphatase which regulates the phosphorylation state of p-tau.  Several of the mTau exosome-specific proteins have been shown to participate in AD mechanisms involving lysosomes, inflammation, secretases, and related processes.  Furthermore, the mTau exosomes lacked a substantial portion of proteins present in control exosomes involved in pathways of localization, vesicle transport, and protein binding functions. The shared proteins present in both mTau and control exosomes represented exosome functions of vesicle-mediated transport, exocytosis, and secretion processes. These data illustrate mTau as a dynamic regulator of the biogenesis of exosomes to result in acquisition, deletion, and up- or down-regulation of protein cargo to result in pathogenic mTau exosomes capable of in vivo propagation of p-tau neuropathology in mouse brain. 

Perlecan is a critical proteoglycan found in the extracellular matrix (ECM) of cartilage. In healthy cartilage, perlecan regulates cartilage biomechanics and we previously demonstrated perlecan deficiency leads to reduced cellular and ECM stiffness in vivo. This change in mechanics may lead to the early onset osteoarthritis seen in disorders resulting from perlecan knockdown such as Schwartz-Jampel syndrome (SJS). To identify how perlecan knockdown affects the material properties of developing cartilage, we used imaging and liquid chromatography–tandem mass spectrometry (LC-MS/MS) to study the ECM in a murine model of SJS, Hspg2C1532Y-Neo. Perlecan knockdown led to defective pericellular matrix formation, whereas the abundance of bulk ECM proteins, including many collagens, increased. Post-translational modifications and ultrastructure of collagens were not significantly different; however, LC-MS/MS analysis showed more protein was secreted by Hspg2C1532Y-Neo cartilage in vitro, suggesting that the incorporation of newly synthesized ECM was impaired. In addition, glycosaminoglycan deposition was atypical, which may explain the previously observed decrease in mechanics. Overall, these findings provide insight into the influence of perlecan on functional cartilage assembly and the progression of osteoarthritis in SJS.

1 October 2007 , Number 7

Chinese goods seem to flood western markets: computers, light bulbs, sweaters, T-shirts and bras. The instinct is to try to protect home producers. A better plan would be to work with Beijing on producing products for the next industrial revolution – the creation of a low-carbon economy. But that would take real vision and political courage.

7 May 2020 , Volume 96, Number 3

Xanthophyllomyces dendrorhous is a basidiomycete yeast known as a natural producer of astaxanthin, a carotenoid of commercial interest because of its antioxidant properties. Recent studies indicated that X. dendrorhous has a functional SREBP pathway involved in the regulation of isoprenoid compound biosynthesis, which includes ergosterol and carotenoids. SREBP is a major regulator of sterol metabolism and homeostasis in mammals; characterization in fungi also provides information about its role in the hypoxia adaptation response and virulence. SREBP protease processing is required to activate SREBP pathway functions in fungi. Here, we identified and described the STP1 gene, which encodes a metallopeptidase of the M50 family involved in the proteolytic activation of the transcription factor Sre1 of the SREBP pathway, in X. dendrorhous. We assessed STP1 function in stp1 strains derived from the wild-type and a mutant of ergosterol biosynthesis that overproduces carotenoids and sterols. Bioinformatic analysis of the deduced protein predicted the presence of characteristic features identified in homologs from mammals and fungi. The stp1 mutation decreased yeast growth in the presence of azole drugs and reduced transcript levels of Sre1-dependent genes. This mutation also negatively affected the carotenoid- and sterol-overproducing phenotype. Western blot analysis demonstrated that Sre1 was activated in the yeast ergosterol biosynthesis mutant and that the stp1 mutation introduced in this strain prevented Sre1 proteolytic activation. Overall, our results demonstrate that STP1 encodes a metallopeptidase involved in proteolytic activation of Sre1 in X. dendrorhous, contributing to our understanding of fungal SREBP pathways.

CVD is the leading cause of death worldwide, and genetic investigations into the human lipidome may provide insight into CVD risk. The aim of this study was to estimate the heritability of circulating lipid species and their genetic correlation with CVD traits. Targeted lipidomic profiling was performed on 4,492 participants from the Busselton Family Heart Study to quantify the major fatty acids of 596 lipid species from 33 classes. We estimated narrow-sense heritabilities of lipid species/classes and their genetic correlations with eight CVD traits: BMI, HDL-C, LDL-C, triglycerides, total cholesterol, waist-hip ratio, systolic blood pressure, and diastolic blood pressure. We report heritabilities and genetic correlations of new lipid species/subclasses, including acylcarnitine (AC), ubiquinone, sulfatide, and oxidized cholesteryl esters. Over 99% of lipid species were significantly heritable (h²: 0.06–0.50) and all lipid classes were significantly heritable (h²: 0.14–0.50). The monohexosylceramide and AC classes had the highest median heritabilities (h² = 0.43). The largest genetic correlation was between clinical triglycerides and total diacylglycerol (r_g = 0.88). We observed novel positive genetic correlations between clinical triglycerides and phosphatidylglycerol species (r_g: 0.64–0.82), and HDL-C and alkenylphosphatidylcholine species (r_g: 0.45–0.74). Overall, 51% of the 4,768 lipid species-CVD trait genetic correlations were statistically significant after correction for multiple comparisons. This is the largest lipidomic study to address the heritability of lipids and their genetic correlation with CVD traits. Future work includes identifying putative causal genetic variants for lipid species and CVD using genome-wide SNP and whole-genome sequencing data.

Lipid rafts are highly ordered regions of the plasma membrane that are enriched in cholesterol and sphingolipids and play important roles in many cells. In hematopoietic stem and progenitor cells (HSPCs), lipid rafts house receptors critical for normal hematopoiesis. Lipid rafts also can bind and sequester kinases that induce negative feedback pathways to limit proliferative cytokine receptor cycling back to the cell membrane. Modulation of lipid rafts occurs through an array of mechanisms, with optimal cholesterol efflux one of the major regulators. As such, cholesterol homeostasis also regulates hematopoiesis. Increased lipid raft content, which occurs in response to changes in cholesterol efflux in the membrane, can result in prolonged receptor occupancy in the cell membrane and enhanced signaling. In addition, certain diseases, like diabetes, may contribute to lipid raft formation and affect cholesterol retention in rafts. In this review, we explore the role of lipid raft-related mechanisms in hematopoiesis and CVD (specifically, atherosclerosis) and discuss how defective cholesterol efflux pathways in HSPCs contribute to expansion of lipid rafts, thereby promoting myelopoiesis and thrombopoiesis. We also discuss the utility of cholesterol acceptors in contributing to lipid raft regulation and disruption, and highlight the potential to manipulate these pathways for therapeutic gain in CVD as well as other disorders with aberrant hematopoiesis.

Sodium glucose co-transporter-2 inhibitors (SGLT2i) have favorable cardiovascular outcomes in diabetic patients. However, whether SGLT2i can improve obesity-related cardiac dysfunction is unknown. Sestrin2 is a novel stress-inducible protein that regulates AMPK-mTOR and suppresses oxidative damage. The aim of this study was to determine whether empagliflozin (EMPA) improves obesity-related cardiac dysfunction via regulating Sestrin2-mediated pathways in diet-induced obesity. C57BL/6J mice and Sestrin2 knockout mice were fed a high-fat diet (HFD) for 12 weeks and then treated with or without EMPA (10 mg/kg) for 8 weeks. Treating HFD-fed C57BL/6J mice with EMPA reduced body weight, whole-body fat, and improved metabolic disorders. Furthermore, EMPA improved myocardial hypertrophy/fibrosis and cardiac function, and reduced cardiac fat accumulation and mitochondria injury. Additionally, EMPA significantly augmented Sestrin2 levels, increased AMPK and eNOS phosphorylation, but inhibited Akt and mTOR phosphorylation. These beneficial effects were partially attenuated in HFD-fed Sestrin2 knockout mice. Intriguingly, EMPA treatment enhanced the Nrf2/HO-1-mediated oxidative stress response, suggesting antioxidant and anti-inflammatory activity. Thus, EMPA improved obesity-related cardiac dysfunction via regulating Sestrin2-mediated AMPK-mTOR signaling and maintaining redox homeostasis. These findings provide a novel mechanism for the cardiovascular protection of SGLT2i in obesity.

Type 2 diabetes mellitus predicts outcome following acute myocardial infarction (AMI). Since underlying mechanics are incompletely understood, we investigated left ventricular (LV) and atrial (LA) pathophysiological changes and their prognostic implications using cardiovascular magnetic resonance (CMR). Consecutive patients (n=1147, n=265 diabetic; n=882 non-diabetic) underwent CMR 3 days after AMI. Analyses included LV ejection fraction (LVEF), global longitudinal, circumferential and radial strains (GLS, GCS and GRS), LA reservoir, conduit and booster pump strains, as well as infarct size, edema and microvascular obstruction. Predefined endpoints were major adverse cardiovascular events (MACE) within 12 months. Diabetic patients had impaired LA reservoir (19.8 vs. 21.2%, p<0.01) and conduit strains (7.6 vs. 9.0%, p<0.01) but not ventricular function or myocardial damage. They were at higher risk of MACE than non-diabetic patients (10.2% vs. 5.8%, p<0.01) with most MACE occurring in patients with LVEF≥35%. Whilst LVEF (p=0.045) and atrial reservoir strain (p=0.024) were independent predictors of MACE in non-diabetic patients, GLS was in diabetic patients (p=0.010). Considering patients with diabetes and LVEF≥35% (n=237), GLS and LA reservoir strain below median were significantly associated with MACE. In conclusion, in patients with diabetes, LA and LV longitudinal strain permit optimized risk assessment early after reperfused AMI with incremental prognostic value over and above LVEF.

Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear if these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we generated transgenic mice with inducible cardiomyocyte-specific expression of the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by O-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct O-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins. These findings identify mitochondria as a major target of glucotoxicity. They also suggest reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

Diabetes is now a pandemic disease. Moreover, a large number of people with prediabetes are at risk for developing frank diabetes worldwide. Both type 1 and type 2 diabetes increase the risk of atherosclerotic cardiovascular disease (CVD). Even with statin treatment to lower LDL cholesterol, patients with diabetes have a high residual CVD risk. Factors mediating the residual risk are incompletely characterized. An attractive hypothesis is that remnant lipoprotein particles (RLPs), derived by lipolysis from VLDL and chylomicrons, contribute to this residual risk. RLPs constitute a heterogeneous population of lipoprotein particles, varying markedly in size and composition. Although a universally accepted definition is lacking, for the purpose of this review we define RLPs as postlipolytic partially triglyceride-depleted particles derived from chylomicrons and VLDL that are relatively enriched in cholesteryl esters and apolipoprotein (apo)E. RLPs derived from chylomicrons contain apoB48, while those derived from VLDL contain apoB100. Clarity as to the role of RLPs in CVD risk is hampered by lack of a widely accepted definition and a paucity of adequate methods for their accurate and precise quantification. New specific methods for RLP quantification would greatly improve our understanding of their biology and role in promoting atherosclerosis in diabetes and other disorders.

The transcription factor forkhead box P3 (FOXP3) is a biomarker for regulatory T cells and can also be expressed in cancer cells, but its function in cancer appears to be divergent. The role of hepatocyte-expressed FOXP3 in hepatocellular carcinoma (HCC) is unknown. Here, we collected tumor samples and clinical information from 115 HCC patients and used five human cancer cell lines. We examined FOXP3 mRNA sequences for mutations, used a luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its tumor-inhibitory capability, and changed cellular responses to histone deacetylase (HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3 mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC.

The actin cytoskeleton is extremely dynamic and supports diverse cellular functions in many physiological and pathological processes, including tumorigenesis. However, the mechanisms that regulate the actin-related protein 2/3 (ARP2/3) complex and thereby promote actin polymerization and organization in cancer cells are not well-understood. We previously implicated the proline-rich 11 (PRR11) protein in lung cancer development. In this study, using immunofluorescence staining, actin polymerization assays, and siRNA-mediated gene silencing, we uncovered that cytoplasmic PRR11 is involved in F-actin polymerization and organization. We found that dysregulation of PRR11 expression results in F-actin rearrangement and nuclear instability in non-small cell lung cancer cells. Results from molecular mechanistic experiments indicated that PRR11 associates with and recruits the ARP2/3 complex, facilitates F-actin polymerization, and thereby disrupts the F-actin cytoskeleton, leading to abnormal nuclear lamina assembly and chromatin reorganization. Inhibition of the ARP2/3 complex activity abolished irregular F-actin polymerization, lamina assembly, and chromatin reorganization due to PRR11 overexpression. Notably, experiments with truncated PRR11 variants revealed that PRR11 regulates F-actin through different regions. We found that deletion of either the N or C terminus of PRR11 abrogates its effects on F-actin polymerization and nuclear instability and that deletion of amino acid residues 100–184 or 100–200 strongly induces an F-actin structure called the actin comet tail, not observed with WT PRR11. Our findings indicate that cytoplasmic PRR11 plays an essential role in regulating F-actin assembly and nuclear stability by recruiting the ARP2/3 complex in human non-small cell lung carcinoma cells.

We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G2-M phase and diminished upon G1 entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRASG12D mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high.

The C-type lectin receptors (CLRs) form a family of pattern recognition receptors that recognize numerous pathogens, such as bacteria and fungi, and trigger innate immune responses. The extracellular carbohydrate-recognition domain (CRD) of CLRs forms a globular structure that can coordinate a Ca2+ ion, allowing receptor interactions with sugar-containing ligands. Although well-conserved, the CRD fold can also display differences that directly affect the specificity of the receptors for their ligands. Here, we report crystal structures at 1.8–2.3 Å resolutions of the CRD of murine dendritic cell-immunoactivating receptor (DCAR, or Clec4b1), the CLR that binds phosphoglycolipids such as acylated phosphatidyl-myo-inositol mannosides (AcPIMs) of mycobacteria. Using mutagenesis analysis, we identified critical residues, Ala136 and Gln198, on the surface surrounding the ligand-binding site of DCAR, as well as an atypical Ca2+-binding motif (Glu-Pro-Ser/EPS168–170). By chemically synthesizing a water-soluble ligand analog, inositol-monophosphate dimannose (IPM2), we confirmed the direct interaction of DCAR with the polar moiety of AcPIMs by biolayer interferometry and co-crystallization approaches. We also observed a hydrophobic groove extending from the ligand-binding site that is in a suitable position to interact with the lipid portion of whole AcPIMs. These results suggest that the hydroxyl group-binding ability and hydrophobic groove of DCAR mediate its specific binding to pathogen-derived phosphoglycolipids such as mycobacterial AcPIMs.

Barbara H. Braffett
May 1, 2020; 69:1000-1010
Complications

Mario Luca Morieri
Apr 1, 2020; 69:771-783
Genetics/Genomes/Proteomics/Metabolomics

Mary C. Gannon
Sep 1, 2004; 53:2375-2382
Pathophysiology

Diabetes Core Update: Covid-19 and Diabetes – Considerations for Health Care Professionals - April 2019

This special issue is an audio version of the American Diabetes Associations Covid-19 leadership team discussing a range of issues on Covid-19 and Diabetes.

Recorded March 31, 2020.

Topics include:

1. Access to medications
2. Effect on Diabetes Self-management
3. Can Patients take their own Supplies if they are an inpatient in the hospital – particularly insulin pumps and CGM
4. Considerations for Specific Hypoglycemic Medications during Inpatient Hospitalization
5. Differences in Management for Persons with Type 1 and Type 2 Diabetes
6. SGLT-2 inhibitors and GLP-1 Receptor Agonists use During Covid-19 Infection
7. Diabetes and Cardiovascular Disease during Covid-19
8. ACEs and ARBs
9. Stress among Healthcare Professionals

Intended for practicing physicians and health care professionals, Diabetes Core Update discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting.

Presented by:

Robert Eckel, MD
ADA President, Medicine & Science
University of Colorado

Mary de Groot, PhD
ADA President, Health Care & Education
Indiana University

Irl Hirsch, MD
University of Washington

Anne Peters, MD
University of Southern California    

Louis Philipson, MD, PhD
ADA Past President, Medicine & Science
University of Chicago

Neil Skolnik, MD
Abington Jefferson Health

This special issue focuses on caring for ourselves while caring for others. 

Recorded April 1, 2020.

This is a part of the American Diabetes Associations ongoing project providing resources for practicing clinicians on the care of Diabetes during the Covid-19 pandemic.  Todays discussion is an audio version of a webinar recorded on April 1, 2020.

Presented by:

Neil Skolnik, M.D.

Abington Jefferson Health

Aaron Sutton

Behavioral Health Consultant

Abington Jefferson Health

This special issue focuses on Cardiovascular Concerns with Diabetes an COVID-19. 

Recorded April 19, 2020.

This is a part of the American Diabetes Associations ongoing project providing resources for practicing clinicians on the care of Diabetes during the Covid-19 pandemic.  Todays discussion is an audio version of a webinar recorded on April 19, 2020.

Presented by:

Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health

John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Chair-Department of Family Medicine, Abington Jefferson Health

Med Treatments India offers one stop solution for medical healthcare services and most affordable treatments facility with best hospitals & alternative treatments in India.

Dance music, Damp heat and talk Drifts to halcyon days of, Seventies groove and Afro’s ruffled, In the political funk of, Freedom fighters and platform shoes, Cadillac language, Smooth and languid, Dripping off honey colored lips like, Melting chocolate… It’s a card trick, And we are mesmorised by, Furtive glances, Over fanned cards, Fascinated by […]

A time will come, When you don’t even, Own your own body, On the side of the road, A full breakdown not a common, Puncture, Leave your heart, it’s broken, Total mechanical failure. What will you do? Trust what you have given? Love, a blue opinion? You have only what you spent. You think you […]

Research Event

Event participants

Dr Jon Gibbins, Senior Lecturer in the Department of Mechanical Engineering, Imperial College London
Jim Footner, Senior Climate Change Campaigner, Greenpeace

1 March 2017

WHAT STARTED as an idea of two Barbadians – Ian Webster and Cheyne Jones – transformed into We Got This, a song which proved enough to stir the collective imagination of 25 recording artistes from 14 countries across the region, disseminating the...